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Research Article

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

View ORCID ProfileShenghui Xue, Hua Yang, Jingjuan Qiao, Fan Pu, Jie Jiang, Kendra Hubbard, Khan Hekmatyar, Jason Langley, Mani Salarian, Robert C. Long, Robert G. Bryant, Xiaoping Philip Hu, Hans E. Grossniklaus, Zhi-Ren Liu, and Jenny J. Yang
  1. Departments of aBiology and
  2. bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
  3. Departments of cOphthalmology and
  4. gRadiology, Emory University, Atlanta, GA 30322;
  5. dInlighta Biosciences LLC, Marietta, GA 30068;
  6. eComplex Carbohydrate Research Center, University of Georgia, Athens, GA 30602;
  7. fCoulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30322; and
  8. hDepartment of Chemistry, University of Virginia, Charlottesville, VA 22904

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PNAS May 26, 2015 112 (21) 6607-6612; first published May 13, 2015; https://doi.org/10.1073/pnas.1423021112
Shenghui Xue
Departments of aBiology and
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
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  • ORCID record for Shenghui Xue
Hua Yang
Departments of cOphthalmology and
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Jingjuan Qiao
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
d Inlighta Biosciences LLC, Marietta, GA 30068;
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Fan Pu
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
d Inlighta Biosciences LLC, Marietta, GA 30068;
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Jie Jiang
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
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Kendra Hubbard
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
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Khan Hekmatyar
eComplex Carbohydrate Research Center, University of Georgia, Athens, GA 30602;
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Jason Langley
fCoulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30322; and
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Mani Salarian
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
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Robert C. Long
gRadiology, Emory University, Atlanta, GA 30322;
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Robert G. Bryant
hDepartment of Chemistry, University of Virginia, Charlottesville, VA 22904
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Xiaoping Philip Hu
fCoulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30322; and
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Hans E. Grossniklaus
Departments of cOphthalmology and
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Zhi-Ren Liu
Departments of aBiology and
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Jenny J. Yang
bChemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
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  • For correspondence: jenny@gsu.edu
  1. Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 20, 2015 (received for review December 2, 2014)

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Significance

Primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents and robust imaging methodologies. We have developed a protein MRI contrast agent (ProCA32) by engineering high-affinity Gd3+-binding pockets in rat and human α-parvalbumin. ProCA32 can function as both a T1- and T2-weighted contrast agent, which enables noninvasive detection of early-stage micrometastatic liver tumors with sizes as small as 0.24 mm using T1- and T2-weighted or T2/T1 ratio MRI. Our protein-based MRI contrast agents and imaging methodology are expected to provide robust results for the early detection of liver cancer as well as other liver diseases.

Abstract

With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd3+ and a 1011-fold greater selectivity for Gd3+ over Zn2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol−1⋅s−1/89.2 mmol−1⋅s−1 per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10–20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.

  • MRI
  • uveal melanoma
  • metastasis
  • contrast agents
  • T2/T1 ratio imaging

Footnotes

  • ↵1To whom correspondence should be addressed. Email: jenny{at}gsu.edu.
  • Author contributions: S.X., X.P.H., H.E.G., Z.-R.L., and J.J.Y. designed research; S.X., H.Y., J.Q., F.P., J.J., K. Hubbard, K. Hekmatyar, J.L., M.S., R.C.L., and R.G.B. performed research; S.X., H.Y., J.L., M.S., X.P.H., H.E.G., and J.J.Y. contributed new reagents/analytic tools; S.X., H.Y., F.P., J.L., R.G.B., X.P.H., H.E.G., Z.-R.L., and J.J.Y. analyzed data; and S.X., R.G.B., Z.-R.L., and J.J.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1423021112/-/DCSupplemental.

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Protein MRI contrast agent for cancer imaging
Shenghui Xue, Hua Yang, Jingjuan Qiao, Fan Pu, Jie Jiang, Kendra Hubbard, Khan Hekmatyar, Jason Langley, Mani Salarian, Robert C. Long, Robert G. Bryant, Xiaoping Philip Hu, Hans E. Grossniklaus, Zhi-Ren Liu, Jenny J. Yang
Proceedings of the National Academy of Sciences May 2015, 112 (21) 6607-6612; DOI: 10.1073/pnas.1423021112

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Protein MRI contrast agent for cancer imaging
Shenghui Xue, Hua Yang, Jingjuan Qiao, Fan Pu, Jie Jiang, Kendra Hubbard, Khan Hekmatyar, Jason Langley, Mani Salarian, Robert C. Long, Robert G. Bryant, Xiaoping Philip Hu, Hans E. Grossniklaus, Zhi-Ren Liu, Jenny J. Yang
Proceedings of the National Academy of Sciences May 2015, 112 (21) 6607-6612; DOI: 10.1073/pnas.1423021112
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